tbuckley/cabot-search huggingface dataset:
Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes
Authors: A Michael Lincoff, Kirstine Brown-Frandsen, Helen M Colhoun, John Deanfield, Scott S Emerson, Sille Esbjerg, Søren Hardt-Lindberg, G Kees Hovingh, Steven E Kahn, Robert F Kushner, Ildiko Lingvay, Tugce K Oral, Marie M Michelsen, Jorge Plutzky, Christoffer W Tornøe, Donna H Ryan
Journal: New England Journal of Medicine (2023)

BackgroundSemaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes. Whether semaglutide can reduce cardiovascular risk associated with overweight and obesity in the absence of diabetes is unknown.MethodsIn a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed.Download a PDF of the Research Summary.ResultsA total of 17,604 patients were enrolled; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The mean (±SD) duration of exposure to semaglutide or placebo was 34.2±13.7 months, and the mean duration of follow-up was 39.8±9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001). Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P<0.001).ConclusionsIn patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months. (Funded by Novo Nordisk; SELECT ClinicalTrials.gov number, NCT03574597.) Quick Take Semaglutide and Cardiovascular Outcomes in Obesity 2m 17s
Re: Pembrolizumab Versus Placebo as Post-nephrectomy Adjuvant Therapy for Clear Cell Renal Cell Carcinoma (KEYNOTE-564): 30-month Follow-up Analysis of a Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 3 Trial
Authors: Carlos Toribio-Vázquez, Luis Martinez-Piñeiro
Journal: European Urology (2023)
Large-Bowel Obstruction from Hereditary Angioedema
Authors: Jane C Y Wong, Philip H Li
Journal: New England Journal of Medicine (2023)

A 37-year-old man presented with a large-bowel obstruction. He reported having had unexplained episodes of abdominal pain and swelling in his hands, feet, and scrotum, without hives or itching, since 18 years of age.
CCDC92 deficiency ameliorates podocyte lipotoxicity in diabetic kidney disease
Authors: Fuwen Zuo, Youzhao Wang, Xinlei Xu, Ruihao Ding, Wei Tang, Yu Sun, Xiaojie Wang, Yan Zhang, Jichao Wu, Yusheng Xie, Min Liu, Ziying Wang, Fan Yi
Journal: Metabolism (2023)

Background and aimsPodocyte injury is considered as the most important early event contributing to diabetic kidney disease (DKD). Recent findings provide new insights into the roles of lipids and lipid-modulating proteins as key determinants of podocyte function in health and kidney disease. CCDC92, a novel member of coiled-coil domain-containing protein family, was indicated relevant to lipid metabolism, coronary heart disease and type 2 diabetes. However, the expression pattern and role of CCDC92 in the kidney is not clear. This study was designed to elucidate the contribution of CCDC92 in the pathogenesis of DKD.MethodsSections with a pathological diagnosis of different classes of DKD, including subjects with mild DKD (class II, n = 6), subjects with moderate DKD (class III, n = 6) or subjects with severe DKD (class IV, n = 6), and control samples (n = 12) were detected for the expression level of CCDC92 and lipid accumulation. Two types of diabetic mice model (db/db and HFD/STZ) in podocyte-specific Ccdc92 knockout background were generated to clarify the role of CCDC92 in podocyte lipotoxicity.ResultsThe level of CCDC92 was increased in renal biopsies sections from patients with DKD, which was correlated with eGFR and lipid accumulation in glomeruli. In animal studies, CCDC92 were also induced in the kidney from two independent diabetic models, especially in podocytes. Podocyte-specific deletion of Ccdc92 ameliorated podocyte injury and ectopic lipid deposition under diabetic condition. Mechanically, CCDC92 promoted podocyte lipotoxicity, at least in part through ABCA1 signaling-mediated lipid homeostasis.ConclusionOur studies demonstrates that CCDC92 acts as a novel regulator of lipid homeostasis to promote podocyte injury in DKD, suggesting that CCDC92 might be a potential biomarker of podocyte injury in DKD, and targeting CCDC92 may be an effective innovative therapeutic strategy for patients with DKD.
A mix &amp; act liposomes of phospholipase A2-phosphatidylserine for acute brain detoxification by blood‒brain barrier selective-opening
Authors: Zinan Zhang, Wenbin Cao, Huanchun Xing, Shuai Guo, Lijuan Huang, Lin Wang, Xin Sui, Kui Lu, Yuan Luo, Yongan Wang, Jun Yang
Journal: Acta Pharmaceutica Sinica B (2023)

In the treatment of central nervous system disease, the blood-brain barrier (BBB) is a major obstruction to drug delivery that must be overcome. In this study, we propose a brain-targeted delivery strategy based on selective opening of the BBB. This strategy allows some simple bare nanoparticles to enter the brain when mixed with special opening material; however, the BBB still maintains the ability to completely block molecules from passing through. Based on the screening of BBB opening and matrix delivery materials, we determined that phospholipase A2-catalyzed 1-palmitoyl-2-oleoyl-
Stimuli‐Responsive 3D Printable Conductive Hydrogel: A Step toward Regulating Macrophage Polarization and Wound Healing
Authors: Jieun Lee, Sayan Deb Dutta, Rumi Acharya, Hyeonseo Park, Hojin Kim, Aayushi Randhawa, Tejal V. Patil, Keya Ganguly, Rachmi Luthfikasari, Ki‐Taek Lim
Journal: Advanced Healthcare Materials (2023)

Abstract Conductive hydrogels (CHs) are promising alternatives for electrical stimulation of cells and tissues in biomedical engineering. Wound healing and immunomodulation are complex processes that involve multiple cell types and signaling pathways. 3D printable conductive hydrogels have emerged as an innovative approach to promote wound healing and modulate immune responses. CHs can facilitate electrical and mechanical stimuli, which can be beneficial for altering cellular metabolism and enhancing the efficiency of the delivery of therapeutic molecules. This review summarizes the recent advances in 3D printable conductive hydrogels for wound healing and their effect on macrophage polarization. This report also discusses the properties of various conductive materials that can be used to fabricate hydrogels to stimulate immune responses. Furthermore, this review highlights the challenges and limitations of using 3D printable CHs for future material discovery. Overall, 3D printable conductive hydrogels hold excellent potential for accelerating wound healing and immune responses, which can lead to the development of new therapeutic strategies for skin and immune‐related diseases.
Critical role of TPRN rings in the stereocilia for hearing
Authors: Jieyu Qi, Fangzhi Tan, Liyan Zhang, Yinyi Zhou, Ziyu Zhang, Qiuhan Sun, Nianci Li, Yuan Fang, Xin Chen, Yunhao Wu, Guisheng Zhong, Renjie Chai
Journal: Molecular Therapy (2023)
Recent application of CRISPR-Cas12 and OMEGA system for genome editing
Authors: Isabel Wen Badon, Yeounsun Oh, Ho-Joong Kim, Seung Hwan Lee
Journal: Molecular Therapy (2023)

In 2012, it was discovered that precise gene editing could be induced in target DNA using the reprogrammable characteristics of the CRISPR system. Since then, several studies have investigated the potential of the CRISPR system to edit various biological organisms. For the typical CRISPR system obtained from bacteria and archaea, many application studies have been conducted and have spread to various fields. To date, orthologs with various characteristics other than CRISPR-Cas9 have been discovered and are being intensively studied in the field of gene editing. CRISPR-Cas12 and its varied orthologs are representative examples of genome editing tools and have superior properties in terms of in vivo target gene editing compared with Cas9. Recently, TnpB and Fanzor of the OMEGA (obligate mobile element guided activity) system were identified to be the ancestor of CRISPR-Cas12 on the basis of phylogenetic analysis. Notably, the compact sizes of Cas12 and OMEGA endonucleases allow adeno-associated virus (AAV) delivery; hence, they are set to challenge Cas9 for in vivo gene therapy. This review is focused on these RNA-guided reprogrammable endonucleases: their structure, biochemistry, off-target effects, and applications in therapeutic gene editing.
Casein kinase 2 activity is a host restriction factor for AAV transduction
Authors: Izabela Kraszewska, Katarzyna Sarad, Kalina Andrysiak, Aleksandra Kopacz, Luisa Schmidt, Marcus Krüger, Józef Dulak, Agnieszka Jaźwa-Kusior
Journal: Molecular Therapy (2023)

So far, the mechanisms that impede AAV transduction, especially in the human heart, are poorly understood, hampering the introduction of new, effective gene therapy strategies. Therefore, the aim of this study was to identify and overcome the main cellular barriers to successful transduction in the heart, using iPSC-derived cardiomyocytes (iPSC-CMs), cardiac fibroblasts (iPSC-CFs), and primary endothelial cells (HAECs) to model vector-host interactions. Through phosphoproteome analysis we established that casein kinase 2 (CK2) signalling is one of the most significantly affected pathways upon AAV exposure. Transient inhibition of CK2 activity substantially enhanced the transduction rate of AAV2, AAV6 and AAV9 in all tested cell types. In particular, CK2 inhibition improved the trafficking of AAVs through the cytoplasm, impaired DNA-damage response through destabilisation of Mre11 and altered the RNA processing pathways, which were also highly responsive to AAV transduction. Also, it augmented transgene expression in already transduced iPSC-CFs, which retain AAV genomes in a functional, but probably silent form. In summary, presented study provides new insights into the current understanding of the host-AAV vector interaction, identifying CK2 activity as a key barrier to efficient transduction and transgene expression, what may translate to improvement the outcome of AAV-based therapies in the future.
Combination HSCT and intravenous AAV-mediated gene therapy in a canine model proves pivotal for translation of Krabbe disease therapy
Authors: Allison M. Bradbury, Jessica Bagel, Gary Swain, Keiko Miyadera, Jill P. Pesayco, Charles-Antoine Assenmacher, Becky Brisson, Ian Hendricks, Xiao H. Wang, Zachary Herbst, Nettie Pyne, Patricia Odonnell, G. Diane Shelton, Michael Gelb, Neil Hackett, Paul Szabolcs, Charles H. Vite, Maria Escolar
Journal: Molecular Therapy (2023)
Pharmacological modulation of vascular ageing: A review from VascAgeNet
Authors: Lynn Roth, Soner Dogan, Bilge Guvenc Tuna, Tamas Aranyi, Sonia Benitez, Maria Borrell-Pages, Perinur Bozaykut, Guido R.Y. De Meyer, Laurent Duca, Nergiz Durmus, Diogo Fonseca, Emil Fraenkel, Philippe Gillery, Alessandro Giudici, Stéphane Jaisson, Madeleine Johansson, Josep Julve, Angela K. Lucas-Herald, Wim Martinet, Pascal Maurice, Barry J. McDonnell, Emine Nur Ozbek, Giacomo Pucci, Christopher J.A. Pugh, Keith D. Rochfort, Anton J.M. Roks, Noemi Rotllan, James Shadiow, Yahya Sohrabi, Bart Spronck, Flora Szeri, Dimitrios Terentes-Printzios, Elif Tunc Aydin, Olga Tura-Ceide, Eda Ucar, Gunay Yetik-Anacak
Journal: Ageing Research Reviews (2023)

Vascular ageing, characterized by structural and functional changes in blood vessels of which arterial stiffness and endothelial dysfunction are key components, is associated with increased risk of cardiovascular and other age-related diseases. As the global population continues to age, understanding the underlying mechanisms and developing effective therapeutic interventions to mitigate vascular ageing becomes crucial for improving cardiovascular health outcomes. Therefore, this review provides an overview of the current knowledge on pharmacological modulation of vascular ageing, highlighting key strategies and promising therapeutic targets. Several molecular pathways have been identified as central players in vascular ageing, including oxidative stress and inflammation, the renin-angiotensin-aldosterone system, cellular senescence, macroautophagy, extracellular matrix remodelling, calcification, and gasotransmitter-related signalling. Pharmacological and dietary interventions targeting these pathways have shown potential in ameliorating age-related vascular changes. Nevertheless, the development and application of drugs targeting vascular ageing is complicated by various inherent challenges and limitations, such as certain preclinical methodological considerations, interactions with exercise training and sex/gender-related differences, which should be taken into account. Overall, pharmacological modulation of endothelial dysfunction and arterial stiffness as hallmarks of vascular ageing, holds great promise for improving cardiovascular health in the ageing population. Nonetheless, further research is needed to fully elucidate the underlying mechanisms and optimize the efficacy and safety of these interventions for clinical translation.
Development and validation of a novel death risk stratification scale in patients with hemorrhagic fever with renal syndrome: a 14-year ambispective cohort study
Authors: Haifeng Hu, Jiayi Zhan, Wenjing Chen, Yali Yang, Hong Jiang, Xuyang Zheng, Jiayu Li, Fei Hu, Denghui Yu, Jing Li, Xiaofei Yang, Ye Zhang, Xiaoyan Wang, Zhanhu Bi, Yan Liang, Huanjun Shen, Hong Du, Jianqi Lian
Journal: Clinical Microbiology and Infection (2023)

To develop and validate a simple and effective death risk stratification scale for hemorrhagic fever with renal syndrome (HFRS).
A Composite Morphometric Duodenal Biopsy Mucosal Scale for Celiac Disease Encompassing Both Morphology and Inflammation
Authors: Jack A. Syage, Markku Mäki, Daniel A. Leffler, Jocelyn A. Silvester, Jennifer A. Sealey-Voyksner, Tsung-Teh Wu, Joseph A. Murray
Journal: Clinical Gastroenterology and Hepatology (2023)

Background & Aims: Villus height to crypt depth ratio (Vh:Cd) and intraepithelial lymphocytes (IEL) are key measures of histology of the small intestine in celiac disease (CeD).While the field of CeD has advanced, there remains no broadly accepted measure of mucosal injury.We assessed whether a composite Vh:Cd and IEL scale (named VCIEL) can improve accuracy and statistical precision for assessing histology, compared to individual measures. Methods:The formulation of the VCIEL composite histologic scale was based on combining the Vh:Cd and IEL measurements for individual patients with equal weighting, by converting each scale to a fraction of their standard deviation and summing the results.The VCIEL formula was applied to several clinical trials and the results for Vh:Cd and IELwere compared to those for VCIEL with regards to clinical significance (effect size) and statistical significance.Results: For the ALV003-1021 trial, we observed an effect size and p-value (ANCOVA) of 1.37, 0.038 for Vh:Cd, 1.17, 0.005 for IEL and 1.86, 0.004 for VCIEL.For the similar glutenchallenge IMGX003-NCCIH-1721 trial, the corresponding results were 0.76, 0.057 for Vh:Cd, 0.98, 0.018 for IEL and 1.14, 0.007 for VCIEL.Similar improvements with the use of VCIEL over individual Vh:Cd and IEL measures were observed for other studies, including a nontherapeutic gluten challenge study. Conclusions:The composite VCIEL scale combining Vh:Cd and IEL values appears to improve accuracy and statistical precision compared to either component alone.
The Legend score synthesizes Wells, PERC, Geneva, D-dimer and predicts acute pulmonary embolism prior to imaging tests
Authors: Yunfeng Zhao, Yi Cheng, Hongwei Wang, He Du, Jinyuan Sun, Mei Xu, Yong Luo, Song Liu, Xuejun Guo, Wei Xiong
Journal: Pulmonology (2023)

The prediction rules of acute pulmonary embolism(PE) before imaging tests recommended by the commonly used guidelines have low diagnostic efficiency if not combined with D-dimer, therefore it is necessary to seek for a prediction rule with higher diagnostic efficiency. We designed a new score named Legend by synthesizing the scores of Wells, PERC, and Geneva, as well as D-dimer with patients in the development group(n = 2112), and then validated it in patients of validation group(n = 388). Diagnostic efficiency was also compared between Legend score and Wells+D-dimer (DD), PERC+DD, Geneva+DD, and YEARS+DD(YEAR algorithm). The Legend score comprised active cancer, D-dimer≥1000 ng/mL, DVT symptoms and/or signs, previous venous thromboembolism (VTE) history, and surgery, trauma, or immobilization in the past month. The sensitivity, specificity, Youden index, and area under the curve(AUC) were 0.985, 0.744, 0.729, and (0.861[0.796–0.925], P<0.001), respectively, for original Legend score, whereas were 0.982, 0.778, 0.760, and (0.871[0.823–0.920], P<0.001), respectively, for simplified Legend score. The Kappa coefficient and P value of McNemar test were 0.988 and 1.000, respectively, between the original and simplified Legend scores. In the validation group, the sensitivity, specificity, Youden index, and C-index were 0.971, 0.749, 0.720, and (0.838[0.781–0.896], P<0.001), respectively, for the original Legend score, whereas were 0.986, 0.715, 0.701, and (0.816[0.750–0.880], P = 0.001) respectively, for the simplified Legend score. The Kappa coefficient and P value of McNemar test between original Legend score and Wells+DD, PERC+DD, Geneva+DD, and YEARS+DD were (0.563, 0.001), (0.139, <0.001), (0.631, 0.006), and (0.732, 0.029), respectively. The Kappa coefficient and P value of McNemar test between simplified Legend score and aforementioned scores were (0.675, 0.009), (0.172, <0.001), (0.747, 0.001), and (0.883, 0.012), respectively. In view of the fact the Legend score reserves the efficient predictors and eliminates the inefficient ones in Wells, PERC, and revised Geneva scores, and incorporates D-dimer into it, a more efficient, modified, and user-friendly one has replaced the original ones. The Legend score yields excellent diagnostic efficiency with good safety in the pretest prediction of acute PE prior to imaging tests. It also avoids more unnecessary imaging tests than Wells+DD, PERC+DD, Geneva+DD, or YEARS+DD.
Cuproptosis: A novel therapeutic target for overcoming cancer drug resistance
Authors: Yumin Wang, Yongming Chen, Junjing Zhang, Yihui Yang, Joshua S. Fleishman, Yan Wang, Jinhua Wang, Jichao Chen, Yuanfang Li, Hongquan Wang
Journal: Drug Resistance Updates (2023)

Cuproptosis is a newly identified form of cell death driven by copper. Recently, the role of copper and copper triggered cell death in the pathogenesis of cancers have attracted attentions. Cuproptosis has garnered enormous interest in cancer research communities because of its great potential for cancer therapy. Copper-based treatment exerts an inhibiting role in tumor growth and may open the door for the treatment of chemotherapy-insensitive tumors. In this review, we provide a critical analysis on copper homeostasis and the role of copper dysregulation in the development and progression of cancers. Then the core molecular mechanisms of cuproptosis and its role in cancer is discussed, followed by summarizing the current understanding of copper-based agents (copper chelators, copper ionophores, and copper complexes-based dynamic therapy) for cancer treatment. Additionally, we summarize the emerging data on copper complexes-based agents and copper ionophores to subdue tumor chemotherapy resistance in different types of cancers. We also review the small-molecule compounds and nanoparticles (NPs) that may kill cancer cells by inducing cuproptosis, which will shed new light on the development of anticancer drugs through inducing cuproptosis in the future. Finally, the important concepts and pressing questions of cuproptosis in future research that should be focused on were discussed. This review article suggests that targeting cuproptosis could be a novel antitumor therapy and treatment strategy to overcome cancer drug resistance.
Simultaneous dendritic cells targeting and effective endosomal escape enhance sialic acid-modified mRNA vaccine efficacy and reduce side effects
Authors: Xueying Tang, Jiashuo Zhang, Dezhi Sui, Qiongfen Yang, Tianyu Wang, Zihan Xu, Xiaoya Li, Xin Gao, Xinyang Yan, Xinrong Liu, Yanzhi Song, Yihui Deng
Journal: Journal of Controlled Release (2023)
Rethinking how development assistance for health can catalyse progress on primary health care
Authors: Tobias Kasper, Gavin Yamey, Sinead Dwyer, Kaci Kennedy McDade, Jon Lidén, Cora Lüdemann, Mohamed Mustafa Diab, Osondu Ogbuoji, Prashant Poodla, Christina Schrade, Andrea Thoumi, Armand Zimmerman, Yibeltal Assefa, Luke N Allen, Paulin Basinga, Patricia J Garcia, Debra Jackson, Henry Mwanyika, Rachel Nugent, Anthony Ofosu, Salman Rawaf, K Srinath Reddy, Dykki Settle, Beth Tritter, Christoph Benn
Journal: The Lancet (2023)
Lepodisiran, an Extended-Duration Short Interfering RNA Targeting Lipoprotein(a)
Authors: Steven E. Nissen, Helle Linnebjerg, Xi Shen, Kathy Wolski, Xiaosu Ma, Shufen Lim, Laura F. Michael, Giacomo Ruotolo, Grace Gribble, Ann Marie Navar, Stephen J. Nicholls
Journal: JAMA (2023)

Epidemiological and genetic data have implicated lipoprotein(a) as a potentially modifiable risk factor for atherosclerotic disease and aortic stenosis, but there are no approved pharmacological treatments.